4-Amino acids of a general formula I, having the 3S-configuration,
especially compound such as (S)-Pregabalin, wherein R3 represents hydrogen, are used for treatment of epilepsy, neuropathic pain, anxiety and social phobia. The pharmacological activity of Pregabalin is primarily attributable to the (S)-enantiomer and thus, several methods have been developed to prepare enantiomerically pure (S)-Pregabalin.
After discovery of the biological activity of (S)-Pregabalin first synthesis has been disclosed in U.S. Pat. No. 5,563,175 and EP 641330. However, the disclosed process is lengthy (more than 10 steps), has a low overall yield and uses pyrophoric or expensive reagents, such as n-butyl lithium or a chiral auxiliary as (+)-4-methyl-5-phenyl-2-oxazolidinone, which definitely limits use on an industrial scale.
In Org. Proc. Res. & Develop. 1997, 1, 26 several other routes to (S)-Pregabalin are reported. Two processes of particular economical interest are disclosed in EPA828704 and EPA830338. In the first patent, 3-isobutyl glutaric acid, prepared from isovaleraldehyde and ethyl cyanoacetate, serves as a key intermediate, which is transformed via the corresponding cyclic anhydride to an amine which can be resolved in a classical manner with chiral phenyl ethylamine. The amide function is then subjected to a Hoffmann degradation leading to (S)-Pregabalin. Improved variations of this process have been disclosed in WO2006/122255, WO2006/122258, WO2006/122259, WO2006/136087, WO2007/035789, WO2007/035790 and WO2007/139933.
In EPA830338 from isovaleraldehyde and diethyl malonate racemic Pregabalin was prepared in five steps and the racemate then resolved. The resolution of the racemate at the end of the synthesis makes the process very costly and inefficient because the (R)-isomer cannot be recycled and has to be discarded. A variation of this process with resolution, prior the reduction of the cyano group, was also disclosed in WO2007/143152. Both processes suffer from disadvantage as lengthy synthesis and low overall yield.
An asymmetric synthesis of an intermediate on the route to (S)-Pregabalin incorporates a homogeneous hydrogenation with chiral phosphine-based ligands (WO2001/55090 and WO2005/087370). The starting material is prepared in 3 steps using carbon monoxide which is hazardous and the phosphine ligands which are very expensive.
In WO2006/110783 conversion of chiral 2-(3-methyl-1-nitro-butyl)-malonic acid dialkyl ester to (S)-Pregabalin using reduction/decarboxylation steps was described. All these processes make use of chiral auxiliaries, catalysts or additives which are often difficult to remove from final product.
Enzymatic kinetic resolution of two nitrile-containing Pregabalin precursors has been claimed in WO2005/100580 and WO2006/00904. In WO2007/143113 also an enzymatic resolution via hydrolysis or esterification of racemic substrates have been reported.
In Synthesis 1989, 953 a synthesis of rac.-Pregabalin, starting from (E)-5-methyl-hex-2-enoic acid ethyl ester, which was converted with nitromethane into 5-methyl-3-nitromethyl-hexanoic acid ethyl ester, has been reported. Subsequent catalytic hydrogenation followed by saponification leads to rac.-Pregabalin. Recently an enzymatic hydrolysis of this racemic nitro ester was carried out (Tetrahedron Asymmetry 2008, 19, 945). With enzyme Novozyme 435 enantiomerically enriched (S)-5-methyl-3-nitromethyl-hexanoic acid could be obtained in a good selectivity if the conversion was stopped at 30%.
In US2010/0197939 a long synthesis of (S)-Pregabalin from D-mannitol has been reported which barely can be used for an industrial production.
The best approaches to (S)-Pregabalin use either prochiral 3-isobutyl glutaric anhydride, which is subjected to a desymmetrization step using either a chiral substrate or an enzyme (WO2007/139933), or a prochiral 3-isobutyl glutaric acid or diester thereof, which have been enzymatically desymmetrised (WO2009/158343).
Although many processes for (S)-Pregabalin are reported, still significant improvements in terms of reducing the number of steps and increasing the overall yields are highly desirable to have an efficient and cost effective manufacturing process.
Of particular interest are specifically enzymatic methods on prochiral substrates: Since the undesired (R)-enantiomer cannot be recycled (racemised) and has to be discarded, enzymatic esterification or hydrolysis of prochiral substrates would allow a complete conversion of the substrate providing exclusively (S)-configurated precursor of (S)-Pregabalin in high yield (90-100%).